In Vivo Evaluation of the Phenox CRC Mechanical Thrombectomy Device in a Swine Model of Acute Vessel Occlusion

Mechanical thrombectomy in ischemic stroke is of increasing interest as it is a promising strategy for fast and efficient recanalization. Several thrombectomy devices have been introduced to the armentarium of mechanical thrombectomy. Currently, new devices are under development and are continuously added to the neurointerventional tool box. Each device advocated so far has a different design and mechanical properties in terms of thrombus-device interaction. Therefore, a systematic evaluation under standardized conditions in vivo of these new devices is needed. The purpose of this study was to evaluate the efficiency, thrombus-device interaction, and potential complications of the novel Phenox CRC for distal mechanical thrombectomy in vivo. The device was evaluated in an established animal model in the swine. Recanalization rate, thromboembolic events, vasospasm, and complications were assessed. Radiopaque thrombi (2 cm length) were used for the visualization of thrombus-device interaction during retrieval. The Phenox CRC (4 mm diameter) was assessed in 15 vessel occlusions. For every occlusion a maximum of 3 retrieval attempts were performed. Complete recanalization (TICI 3/TIMI 3) was achieved in 86.7% of vessel occlusions. In 66.7% (10/15), the first retrieval attempt was successful, and in 20% (3/15), the second attempt led to complete recanalization of the parent artery. In 2 cases (13.3%) thrombus retrieval was not successful (TICI 0/TIMI 0). In 1 case (6.7%) a minor embolic event occurred in a small side branch. No distal thromboembolic event was observed during the study. Thrombus-device interaction illustrated the entrapment of the thrombus by the microfilaments and the proximal cage of the device. No significant thrombus compression was observed. No vessel perforation, dissection, or fracture of the device occurred. In this small animal study, the Phenox CRC was a safe and effective device for mechanical thrombectomy. The unique design with a combination of microfilaments and proximal cage reduces thrombus compression with a consequently high recanalization and low complication rate.

In vivo evaluation of the first dedicated combined flow-restoration and mechanical thrombectomy device in a swine model of acute vessel occlusion

The use of self-expanding retrievable stents is an emerging and promising treatment strategy for acute stroke treatment. The concept combines the advantages of stent deployment with immediate flow-restoration and of mechanical thrombectomy with definitive thrombus removal. The present study was performed to gain more knowledge about the principle of combined flow restoration and thrombectomy in an established animal model using radiopaque thrombi evaluating efficiency, thrombus-device interaction and possible complications of the first dedicated flow-restoration and mechanical thrombectomy device.

National institutes of health stroke scale score and vessel occlusion in 2152 patients with acute ischemic stroke

Background and Purpose—There is some controversy on the association of the National Institutes of Health Stroke Scale (NIHSS) score to predict arterial occlusion on MR arteriography and CT arteriography in acute stroke. Methods—We analyzed NIHSS scores and arteriographic findings in 2152 patients (35.4% women, mean age 66±14 years) with acute anterior or posterior circulation strokes. Results—The study included 1603 patients examined with MR arteriography and 549 with CT arteriography. Of those, 1043 patients (48.5%; median NIHSS score 5, median time to clinical assessment 179 minutes) showed an occlusion, 887 in the anterior (median NIHSS score 7/0–31), and 156 in the posterior circulation (median NIHSS score 3/0–32). Eight hundred sixty visualized occlusions (82.5%) were located centrally (ie, in the basilar, intracranial vertebral, internal carotid artery, or M1/M2 segment of the middle cerebral artery). NIHSS scores turned out to be predictive for any vessel occlusions in the anterior circulation. Best cut-off values within 3 hours after symptom onset were NIHSS scores ≥9 (positive predictive value 86.4%) and NIHSS scores ≥7 within >3 to 6 hours (positive predictive value 84.4%). Patients with central occlusions presenting within 3 hours had NIHSS scores <4 in only 5%. In the posterior circulation and in patients presenting after 6 hours, the predictive value of the NIHSS score for vessel occlusion was poor. Conclusions—There is a significant association of NIHSS scores and vessel occlusions in patients with anterior circulation strokes. This association is best within the first hours after symptom onset. Thereafter and in the posterior circulation the association is poor.

Vascular endothelial cell-specific phosphotyrosine phosphatase (VE-PTP) activity is required for blood vessel development

VE-PTP, a receptor-type phosphotyrosine phosphatase, associates with the tyrosine kinase receptor Tie-2 and VE-cadherin and enhances the adhesive function of the latter. Here, VE-PTP was found to be restricted to endothelial cells, with a preference for arterial endothelium. Mutant mice expressing a truncated, secreted form of VE-PTP lacking the cytoplasmic and transmembrane domains and the most membrane-proximal extracellular fibronectin type III repeat, showed severe vascular malformations causing lethality at 10 days of gestation. Although blood vessels were initially formed, the intraembryonic vascular system soon deteriorated. Blood vessels in the yolk sac developed into dramatically enlarged cavities. In explant cultures of mutant allantoides, endothelial cells were found next to vessel structures growing as cell layers. No signs for enhanced endothelial apoptosis or proliferation were observed. Thus, the activity of VE-PTP is not required for the initial formation of blood vessels, yet it is essential for their maintenance and remodeling.

Percutaneous transluminal angioplasty and stent placement in acute vessel occlusion: evaluation of new methods for interventional stroke treatment

BACKGROUND AND PURPOSE: The major goal of acute ischemic stroke treatment is fast and sufficient recanalization. Percutaneous transluminal balloon angioplasty (PTA) and/or placement of a stent might achieve both by compressing the thrombus at the occlusion site. This study assesses the feasibility, recanalization rate, and complications of the 2 techniques in an animal model. MATERIALS AND METHODS: Thirty cranial vessels of 7 swine were occluded by injection of radiopaque thrombi. Fifteen vessel occlusions were treated by PTA alone and 15, by placement of a stent and postdilation. Recanalization was documented immediately after treatment and after 1, 2, and 3 hours. Thromboembolic events and dissections were documented. RESULTS: PTA was significantly faster to perform (mean, 16.6 minutes versus 33.0 minutes for stent placement; P < .001), but the mean recanalization rate after 1 hour was significantly better after stent placement compared with PTA alone (67.5% versus 14.6%, P < .001). Due to the self-expanding force of the stent, vessel diameter further increased with time, whereas the recanalization result after PTA was prone to reocclusion. Besides thromboembolic events related to the passing maneuvers at the occlusion site, no thrombus fragmentation and embolization occurred during balloon inflation or stent deployment. Flow to side branches could also be restored at the occlusion site because it was possible to direct thrombus compression. CONCLUSIONS: Stent placement and postdilation proved to be much more efficient in terms of acute and short-term vessel recanalization compared with PTA alone.

VE-PTP controls blood vessel development by balancing Tie-2 activity

Vascular endothelial protein tyrosine phosphatase (VE-PTP) is an endothelial-specific receptor-type tyrosine phosphatase that associates with Tie-2 and VE-cadherin. VE-PTP gene disruption leads to embryonic lethality, vascular remodeling defects, and enlargement of vascular structures in extraembryonic tissues. We show here that antibodies against the extracellular part of VE-PTP mimic the effects of VE-PTP gene disruption exemplified by vessel enlargement in allantois explants. These effects require the presence of the angiopoietin receptor Tie-2. Analyzing the mechanism we found that anti-VE-PTP antibodies trigger endocytosis and selectively affect Tie-2-associated, but not VE-cadherin-associated VE-PTP. Dissociation of VE-PTP triggers the activation of Tie-2, leading to enhanced endothelial cell proliferation and enlargement of vascular structures through activation of Erk1/2. Importantly, the antibody effect on vessel enlargement is also observed in newborn mice. We conclude that VE-PTP is required to balance Tie-2 activity and endothelial cell proliferation, thereby controlling blood vessel development and vessel size.

Cell-demanded liberation of VEGF121 from fibrin implants induces local and controlled blood vessel growth

Although vascular endothelial growth factor (VEGF) has been described as a potent angiogenic stimulus, its application in therapy remains difficult: blood vessels formed by exposure to VEGF tend to be malformed and leaky. In nature, the principal form of VEGF possesses a binding site for ECM components that maintain it in the immobilized state until released by local cellular enzymatic activity. In this study, we present an engineered variant form of VEGF, alpha2PI1-8-VEGF121, that mimics this concept of matrix-binding and cell-mediated release by local cell-associated enzymatic activity, working in the surgically-relevant biological matrix fibrin. We show that matrix-conjugated alpha2PI1-8-VEGF121 is protected from clearance, contrary to native VEGF121 mixed into fibrin, which was completely released as a passive diffusive burst. Grafting studies on the embryonic chicken chorioallantoic membrane (CAM) and in adult mice were performed to assess and compare the quantity and quality of neovasculature induced in response to fibrin implants formulated with matrix-bound alpha2PI1-8-VEGF121 or native diffusible VEGF121. Our CAM measurements demonstrated that cell-demanded release of alpha2PI1-8-VEGF121 increases the formation of new arterial and venous branches, whereas exposure to passively released wild-type VEGF121 primarily induced chaotic changes within the capillary plexus. Specifically, our analyses at several levels, from endothelial cell morphology and endothelial interactions with periendothelial cells, to vessel branching and network organization, revealed that alpha2PI1-8-VEGF121 induces vessel formation more potently than native VEGF121 and that those vessels possess more normal morphologies at the light microscopic and ultrastructural level. Permeability studies in mice validated that vessels induced by alpha2PI1-8-VEGF121 do not leak. In conclusion, cell-demanded release of engineered VEGF121 from fibrin implants may present a therapeutically safe and practical modality to induce local angiogenesis.

Blood vessel anomalities in the oral cavity of two calves

Two calves were presented with a congenital mass in the rostral mandibular gingiva. In both cases the masses relapsed after surgical removal. Histologically, the two masses were composed of irregularly arranged vascular cavities, embedded in loosely arranged stroma and alcian-blue PAS positive ground substance. Radiologically, a destruction of the alveolar cavity was recognized in both cases, which was in case 1 histologically compatible with bone resorption and remodeling associated with the infiltration of abundant granulation tissue. A literature survey revealed that no consistent criteria for a correct classification for vascular tumours exists, resulting in the fact that comparable lesions were named differently in the past. We therefore propose to classify such lesions as congential vascular malformation until distinct morphological, immunohistochemical and molecular genetic analysis criteria will exist.

Clinical prediction of large vessel occlusion in anterior circulation stroke: mission impossible?

Simple clinical scores to predict large vessel occlusion (LVO) in acute ischemic stroke would be helpful to triage patients in the prehospital phase. We assessed the ability of various combinations of National Institutes of Health Stroke Scale (NIHSS) subitems and published stroke scales (i.e., RACE scale, 3I-SS, sNIHSS-8, sNIHSS-5, sNIHSS-1, mNIHSS, a-NIHSS items profiles A-E, CPSS1, CPSS2, and CPSSS) to predict LVO on CT or MR arteriography in 1085 consecutive patients (39.4 % women, mean age 67.7 years) with anterior circulation strokes within 6 h of symptom onset. 657 patients (61 %) had an occlusion of the internal carotid artery or the M1/M2 segment of the middle cerebral artery. Best cut-off value of the total NIHSS score to predict LVO was 7 (PPV 84.2 %, sensitivity 81.0 %, specificity 76.6 %, NPV 72.4 %, ACC 79.3 %). Receiver operating characteristic curves of various combinations of NIHSS subitems and published scores were equally or less predictive to show LVO than the total NIHSS score. At intersection of sensitivity and specificity curves in all scores, at least 1/5 of patients with LVO were missed. Best odds ratios for LVO among NIHSS subitems were best gaze (9.6, 95 %-CI 6.765-13.632), visual fields (7.0, 95 %-CI 3.981-12.370), motor arms (7.6, 95 %-CI 5.589-10.204), and aphasia/neglect (7.1, 95 %-CI 5.352-9.492). There is a significant correlation between clinical scores based on the NIHSS score and LVO on arteriography. However, if clinically relevant thresholds are applied to the scores, a sizable number of LVOs are missed. Therefore, clinical scores cannot replace vessel imaging.

Applicability of Tableside Flat Panel Detector CT Parenchymal Cerebral Blood Volume Measurement in Neurovascular Interventions: Preliminary Clinical Experience

CBV is a vital perfusion parameter in estimating the viability of brain parenchyma (eg, in cases of ischemic stroke or after interventional vessel occlusion). Recent technologic advances allow parenchymal CBV imaging tableside in the angiography suite just before, during, or after an interventional procedure. The aim of this work was to analyze our preliminary clinical experience with this new imaging tool in different neurovascular interventions.

Monitoring cerebral oxygenation during balloon occlusion with multichannel NIRS

We report on oxygenation changes noninvasively recorded by multichannel continuous-wave near infrared spectroscopy (CW-NIRS) during endovascular neuroradiologic interventions requiring temporary balloon occlusion of arteries supplying the cerebral circulation. Digital subtraction angiography (DSA) provides reference data on the site, timing, and effectiveness of the flow stagnation as well as on the amount and direction of collateral circulation. This setting allows us to relate CW-NIRS findings to brain specific perfusion changes. We focused our analysis on the transition from normal perfusion to vessel occlusion, i.e., before hypoxia becomes clinically apparent. The localization of the maximal response correlated either with the core (occlusion of the middle cerebral artery) or with the watershed areas (occlusion of the internal carotid artery) of the respective vascular territories. In one patient with clinically and angiographically confirmed insufficient collateral flow during carotid artery occlusion, the total hemoglobin concentration became significantly asymmetric, with decreased values in the ipsilateral watershed area and contralaterally increased values. Multichannel CW-NIRS monitoring might serve as an objective and early predictive marker of critical perfusion changes during interventions-to prevent hypoxic damage of the brain. It also might provide valuable human reference data on oxygenation changes as they typically occur during acute stroke.

Outcome of acute stroke patients without visible occlusion on early arteriography

BACKGROUND: The aim of this study was to determine the clinical and radiological outcome of acute stroke patients who had no vessel occlusion on arteriography and to define predictors of clinical outcome. METHODS: We analyzed clinical and radiological data of stroke patients whose arteriography performed within 6 hours of symptom onset did not visualize any vessel occlusion. RESULTS: Twenty-eight of 283 consecutive patients (10%) who underwent arteriography with the intention to perform intraarterial thrombolysis did not show any arterial occlusion. Their median baseline National Institutes of Health Stroke Scale (NIHSS) score was 7. Time from symptom onset to arteriography ranged from 115 to 315 minutes; on average, it was 226 minutes. Presumed stroke cause was cardiac embolism in 11 patients (39%), small artery disease in 6 (21%), coronary angiography in 1 (4%), and undetermined in 10 patients (36%). After 3 months, modified Rankin Scale score (mRS) was < or =2 in 21 patients (75%), indicating a favorable outcome. Six patients (21%) had a poor outcome (mRS 3 or 4) and 1 patient (4%) had a myocardial infarction and died. Twenty-seven patients had follow-up brain imaging. It was normal in 5, showed a lacunar lesion in 8, a striatocapsular infarct in 2, a small or medium-sized anterior circulation infarct in 6, multiple small anterior circulation infarcts in 2, and multiple posterior circulation infarcts in 4. No predictors of clinical outcome were identified. CONCLUSIONS: Most acute stroke patients with normal early arteriography show infarcts on brain imaging; however, clinical outcome is usually favorable.

Imaging of acute ischemic stroke.

BACKGROUND Over 80% of strokes result from ischemic damage to the brain due to an acute reduction in the blood supply. Around 25-35% of strokes present with large vessel occlusion, and the patients in this category often present with severe neurological deficits. Without early treatment, the prognosis is poor. Stroke imaging is critical for assessing the extent of tissue damage and for guiding treatment. SUMMARY This review focuses on the imaging techniques used in the diagnosis and treatment of acute ischemic stroke, with an emphasis on those involving the anterior circulation. Key Message: Effective and standardized imaging protocols are necessary for clinical decision making and for the proper design of prospective studies on acute stroke. CLINICAL IMPLICATIONS Each minute without treatment spells the loss of an estimated 1.8 million neurons ('time is brain'). Therefore, stroke imaging must be performed in a fast and efficient manner. First, intracranial hemorrhage and stroke mimics should be excluded by the use of computed tomography (CT) or magnetic resonance imaging (MRI). The next key step is to define the extent and location of the infarct core (values of >70 ml, >1/3 of the middle cerebral artery (MCA) territory or an ASPECTS score ≤ 7 indicate poor clinical outcome). Penumbral imaging is currently based on the mismatch concept. It should be noted that the penumbra is a dynamic zone and can be sustained in the presence of good collateral circulation. A thrombus length of >8 mm predicts poor recanalization after intravenous thrombolysis.

The use of flat panel angioCT (DynaCT) for navigation through a deformed and fractured carotid stent

Navigation through a previously deployed and deformed stent is a difficult interventional task. Inadvertent navigation through the struts of a stent can potentially lead to incomplete secondary stent extension and vessel occlusion. Better visualisation of the pathway through the stent can reduce the risks of the procedural complications and reduce the reluctance of the interventionalist to navigate through a previously deployed stent. We describe a technique of visualisation of the pathway navigated by a guidewire through a previously deployed deformed and fractured carotid stent by the use of DynaCT. Three-dimensional reconstruction of the stent/microwire allows excellent visualisation of the correct pathway of the microwire within the stent.

Predictors of early mortality after acute ischaemic stroke.

BACKGROUND The study set out to identify clinical, laboratory and radiological predictors of early mortality after an acute ischaemic stroke (AIS) and to analyse medical and neurological complications that caused death. METHODS A total of 479 consecutive patients (mean age 63+/-14 years) with AIS underwent stroke examination and treatment. Examination included clinical evaluation, laboratory tests, and brain CT and/or MRI. Follow-up data at 30 days were available for 467 patients (93%) who were included in the present analysis. RESULTS The median National Institute of Health Stroke Study (NIHSS) score on admission was 6. A total of 62 patients (13%) died within 30 days. The cause of death was the initial event in 43 (69%), pneumonia in 12 (19%), intracerebral haemorrhage in 9 (15%), recurrent stroke in 6 (10%), myocardial infarction in 2 (3%), and cancer in 1 (2%) of the patients. In univariate comparisons, advanced age (p<0.001), hypertension (p=0.013), coronary disease (p=0.001), NIHSS score (p<0.001), undetermined stroke etiology (p=0.031), relevant co-morbidities (p=0.008), hyperglycemia (p<0.001), atrial fibrillation (p<0.001), early CT signs of ischemia (p<0.001), dense artery sign (p<0.001), proximal vessel occlusion (p<0.001), and thrombolysis (p=0.008) were associated with early mortality. In multivariate analysis, advanced age (HR=1.12; 95% CI 1.05-1.19; p<0.001) and high NIHSS score on admission (HR=1.15, 95% CI 1.05-1.25; p=0.002) were independent predictors of early mortality. CONCLUSIONS We report 13% mortality at 30 days after AIS. More than two thirds of the deaths are related to the initial stroke. Advanced age and high NIHSS score are the only independent predictors of early mortality in this series.